This laboratory has focused on the elucidation of fundamental molecular mechanisms that are involved in immune activation. In particular we have studied the genetic response of mitogenically activated T cells. We cloned by subtraction technology many novel genes induced immediately after stimulation of primary human T cells. They encode transcription factors, cytokines, transmembrane receptors, a nuclear tyrosine phosphatase, and a ras-related protein. Recently we have focused our efforts primarily on NF-kappaB, one of the transcription factors we cloned. NF-kappaB is an essential transcriptional regulator of immune/defensive responses. NF-kappaB is a family of dimeric complexes that are composed of members of the Rel/NF-kappaB family of polypeptides. NF-kappaB lies dormant in the cytoplasm of unstimulated cells, kept there by inhibitory IkappaB proteins. Upon stimulation, NF-kappaB is released into the nucleus within minutes to potentially induce the transcription of numerous immunomodulatory genes. We have previously determined that appropriate cellular stimulation leads to rapid phosphorylation and proteolytic degradation of I~B, allowing NF-kappaB to enter nuclei. We also discovered that the activated NF-kappaB immediately induces its own inhibitor in a negative autoregulatory loop; in this way a transient response is assured. We have now determined that the proteolytic degradation of IkappaB is an integral part of the activation process, since NF-kappaB remains associated with IkappaB even after phosphorylation of the inhibitor. Therefore, IkappaB proteases provide a potential therapeutic target to block activation of NF-kappaB in order to control inflammatory conditions. We have begun to define the molecular mechanisms by which the human T lymphotropic virus type 1 Tax product activates NF-kappaB; the activation of NF-kappaB is thought to be essential for the transformation of T cells which precedes the onset of adult T cell leukemia. Tax significantly increases the turnover of the IkappaB inhibitor, and thus weakens cytoplasmic retention of NF- kappaB. In addition, tax liberates some NF-kappaB complexes for nuclear translocation by antagonizing the IkappaB-like cytoplasmic sequestration function of p100. Therefore two separate Tax-mediated mechanisms may contribute to maintain high levels of nuclear NF-kappaB.